The objective of the proposed research is to examine the role of 5-HT systems in cocaine-seeking behavior using the extinction/reinstatement model. Animals will be trained to self-administer cocaine or will receive yoked administration of saline for 14 days. Later, drug-seeking behavior will be assessed during three phases: 1) extinction of drug-seeking behavior, 2) reinstatement of drug-seeking behavior by presentation of cues previously paired with cocaine infusions, and 3) reinstatement of drug-seeking behavior by cocaine (15mg/kg.IP.) The first experiment will examine the effects of 5-HT depletion on extinction and cue-elicited reinstatement of drug-seeking behavior during a 21-day treatment period. Changes in the density of 5-HT1A, 5-HT1B, 5-HT2, and 5-HT3 receptors in various limbic areas will also be examined using quantitative autoradiography. It is predicted that 5-HT depletion will increase resistance to extinction and enhance cocaine-seeking behavior. In contrast it is predicted that chronic fluoxetine treatment will decrease resistance extinction and attenuate cocaine-seeking behavior. Findings from these experiments can be applied to develop effective pharmacologic treatment for cocaine craving and relapse.